Administration of therapeutic or diagnostic agents using interlabial pad

ABSTRACT

A method is disclosed for administering an agent (for example delivering a drug or diagnostic agent) intravaginally or to the interlabial space by positioning an interlabial device, such as an absorbent pad, between the labia. The pad is retained between the labia for a sufficient period of time to deliver an active agent, or allow a reaction with a diagnostic agent. Alternatively, the pad is applied after medication is administered, for example intravaginally or labially or perilabially, to help reduce discomfort to the subject, or loss of medication. The active agent may be carried by the pad itself, or in an intravaginal extension of the pad, or separately in a suppository or other dosage form. In particular examples, the pad has a smaller minor portion superimposed on a larger major portion, and the smaller minor portion is inserted as a leading edge between the labia of the subject to facilitate interlabial insertion. In another example, the pad is placed interlabially after insertion of an agent (such as a medicated suppository) into the vagina, to inhibit loss of the medication from the vagina. The pad can have a variety of shapes, including major and minor portions that are portions of spheres or ellipsoids, or which are elongated and have cross-sections that are circular or ellipsoid, or pads which are folded.

PRIORITY CLAIM

This is a continuation of U.S. application Ser. No. 09/788,264, filedFeb. 16, 2001, which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to a drug delivery device, and more particularlyto such a device that is capable of interlabial drug delivery, forexample interlabial or perilabial drug delivery, or can be used as anadjunct in the delivery of drugs.

BACKGROUND OF THE INVENTION

The female external genitalia includes the interlabial space, locatedbetween the inside surfaces of the labia majora and extending past thevestibule of the vagina. Located within this interlabial space are thelabia minora, clitoris, urethral orifice, and vaginal orifice. Theinterlabial space is covered by a thin layer of keratinized epithelium.

A variety of diseases affect the interlabial space in human females.Infectious diseases include vaginitis, herpes simplex virus-2 (HSV-2),human papillomavirus (HPV), syphilis, and candidiasis. Dysplastic andhyperplastic conditions include postmenopausal atrophy, squamous cellhyperplasia, and lichen sclerosus. Precancerous and cancerous conditionsinclude vulvar intraepithelial neoplasia and vulvar carcinoma. Thesediseases result in serious health problems, including pain, itching,disfigurement and possibly even death.

Currently, therapy for vulvar diseases is delivered either systemicallyor locally. Examples of systemic therapy include oral acyclovir forHSV-2 infection, and intramuscular penicillin-G for primary syphilis.Local therapy includes a variety of creams, ointments, and solutionscontaining corticosteroids, antifungal agents, hormones, and othermedicinal agents.

Although both forms of therapy have shown favorable effects on manyvulvar diseases, both have limitations. Systemic therapy carries therisk of systemic side effects, and the effectiveness of local therapyhas been limited by the need for frequent applications, messiness, andpoor patient compliance. There is a need, therefore, for a simple andeffective approach to local therapy of vulvar diseases. At the sametime, there is a need for more efficient, convenient and comfortablesystemic administration of drugs, whether or not they are intended forthe treatment of vulvar pathologies.

Feminine hygiene pads consisting of various layers of absorbentmaterials are used primarily to absorb uncontrolled discharges duringmenstruation. These pads have taken the form of thick elongated femininenapkins which are primarily used during the early stages of themenstrual cycle and narrow absorbent tubes, known as tampons, which areinserted into the vagina and which are used primarily during the latterstages of the menstrual cycle.

SUMMARY OF THE DISCLOSURE

The methods and devices of the present invention take advantage of acompletely new use of absorbent interlabial pads, namely theadministration of therapeutic and diagnostic agents, such aspharmaceutically active agents or diagnostic reagents. It has been foundthat local and transdermal administration of many different agents canbe facilitated by application of the drug to the labia. However, becauseof the complex and sensitive anatomy of the perineum and associatedlabial tissue, it has been difficult to administer agents in thisfashion. Moreover, the labial and perilabial area is frequently the siteof infection and inflammation (such as that caused by fungal orbacterial infections, such as vaginitis, or exposure to feces or urine).Although topical ointments can be applied to the perineum and labia,such topical administration is often messy and stains undergarments. Inaddition, intravaginal suppositories leak from the vagina, resulting inloss of some therapeutic efficacy, and discomfort to the subject.

The present invention has solved many of these problem, by providing asystem or device for administering agents (such as pharmaceuticallyactive substances or diagnostic reagents), wherein the device isconfigured to be retained between the labia of a subject. The deviceeither carries a therapeutically or diagnostically effective amount ofan agent to be delivered, or is placed interlabially after an agent hasbeen applied, for example to the external genitalia or intravaginally(as with a suppository). In one example, the device includes aninterlabial pad, which is retained in the interlabial space forsustained contact with the labial skin and/or vaginal orifice. Thissustained contact conforms to the complex external genital and perinealanatomy, without causing additional discomfort. Moreover, the system isable to function as a self-contained transdermal interlabial drugdelivery system which targets the delivery of certain medications to thelabia and/or vagina, substantially without staining undergarments orinadvertently delivering the drug to the surrounding perineum andthighs. The pad can be retained in the interlabial space, without theuse of a supporting garment or adhesive. In particular embodiments, thepad is positioned external to the vaginal orifice, so that it is notretained by insertion into the vagina. However, in other embodiments, aportion of the pad can project at least partially into the vagina fortargeted delivery of drug to the intravaginal space.

In another embodiment, the delivery device includes an intravaginalportion and an extravaginal portion. The extravaginal portion caninclude an interlabial pad that is retained between the labia, and theintravaginal portion (such as a medicated extension or suppository)delivers medication intravaginally.

Although targeted local delivery of active agents is possible,particularly for an agent having low lipid permeability and lowtransdermal flux, the delivery system can also be used for systemicdelivery of pharmaceutical agents through the labial skin, or viavaginal absorption.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of the perineum and thighs, which illustratesthe external female genitalia.

FIG. 2 is a cross-sectional sagittal view taken along line 2-2 of FIG.1, but showing a pad positioned between the labia.

FIG. 3 is a schematic view of one embodiment of the interlabial drugdelivery device.

FIG. 4 is a cross sectional fragmentary view of another embodiment ofthe interlabial drug delivery pad.

FIGS. 5-9 are views similar to FIG. 4, but showing different embodimentsof the pad which have a substantially quadrilateral shape.

FIGS. 10 and 11 are cross sectional views of the major portion of thepad, showing the major portion to be either arcuate (FIG. 10) or tapered(FIG. 11).

FIG. 12 is a cross sectional view of an interlabial absorbent pad thatdoes not have a major portion and a minor portion, but which has theside surfaces of the pad sloping toward a leading edge of the pad.

FIGS. 13-15 are cross-sectional fragmentary views showing pads whichhave major portions that are polygonal in shape.

FIG. 16 is a cross sectional view of an elongated interlabial pad with amajor portion and a minor portion, both of which taper symmetrically ina longitudinal direction.

FIG. 17 is a view similar to FIG. 16, but showing the major and minorportions of the pad tapering longitudinally in different directions.

FIG. 18 is a perspective view of an elongated interlabial absorbent padthat has a fixed diameter along the length of the pad.

FIGS. 19-21 are side views of interlabial absorbent pads similar to thepad shown in FIGS. 18, but with one or two sloping end edges.

FIG. 22 is a cross sectional view of an interlabial absorbent padwherein the posterior portion of the pad is formed with a longitudinalgroove.

FIG. 23 is a cross sectional view of the interlabial absorbent pad ofFIG. 22 disposed between the labia in the interlabial space.

FIG. 24 is a cross sectional view of a unitary, one-piece yet bipartiteinterlabial absorbent pad in which each portion of the pad has a crosssection of a portion of a circle, each circle having different radii ofcurvature. FIG. 25 is a cross sectional view of a bipartite pad in whicheach portion of the pad has a cross section of a partial ellipse. Thepads may be either symmetric or asymmetric. In the symmetric embodiment,the major and minor portions may have the shape of partial spheres orellipsoids.

FIG. 26 is a cross sectional view of an additional embodiment of aone-piece interlabial pad with an elliptical cross section, and no minorand major portions.

FIG. 27 is an end perspective view of an elongated pad with a minor anda major portion that extends along its length, and a groove in the minorportion from which drugs or other agents can be released by compressionof the pad in use.

FIG. 28 is an end view of the pad of FIG. 27.

FIG. 29 is a perspective view of an elongated folded pad.

FIG. 30 is an end view of the pad of claim 29.

FIG. 31 is a perspective view of an elongated pad.

FIG. 32A is an MRI of an external feminine hygiene pad in place againstthe external female genitalia.

FIG. 32B is an MRI of an example of a pad in accordance with the presentdisclosure, in which the pad is retained between the labia, external tothe hymenal ring

FIG. 33 is a schematic diagram of a system for making the applicationdevices.

FIG. 34 is a schematic diagram of a liquid application system forapplying liquid agents to the application devices.

DESCRIPTION OF MULTIPLE SPECIFIC EXAMPLES

The interlabial pad is used in a method of delivery of a therapeutic ordiagnostic agent (such as a drug or diagnostic reagent) by positioningthe absorbent pad between the labia, external to the subject's vaginalorifice, such that the pad is retained between and by the labia. Inparticular embodiments of this method, the pad is devoid of corners andflat surfaces intermediate its ends, and the pad has a minor portionsuperimposed on a major portion. The minor portion of the pad has across-sectional area or width that is smaller than a cross-sectionalarea or width of the major portion, and both the minor and the majorportions are curvilinear or partially cylindrical in cross-section. Thereduced width minor portion facilitates insertion of the pad between thesubject's labia, separation of the labia, and placement of the smallerportion adjacent the vaginal orifice. The larger major portion conformsto the interlabial space, and helps hold the pad frictionally engaged inthe space.

An example of an interlabial pad useful with the present methods is theinterlabial pad developed by A-Fem Medical Corporation. Various forms ofinterlabial pads, as well as methods of producing them, are described inU.S. Pat. Nos. 3,983,873, 4,095,542 and 4,142,476. These pads aredesigned to be placed longitudinally between the vaginal lips or labia,and are particularly useful to absorb light discharges of menstrualfluids, mid-cycle spotting or discharges, slight loss of urine caused byphysical stress, or leakages following intercourse.

Methods and devices for manufacturing feminine hygiene interlabial padsare described in U.S. Pat. No. 4,995,150, which patent is herebyincorporated herein by reference. However, in the embodiment as setforth in U.S. Pat. No. 4,995,150, it is taught that the outer coveringbe made of a heat-sealable material such as polypropylene, which is noteasily biodegradable. A biodegradable interlabial pad is disclosed inU.S. Pat. No. 5,575,047, which is also incorporated by reference. Thebiodegradable pad is capable of being decomposed by natural biologicalprocesses.

Another example of an interlabial pad suitable for use with the presentmethod is the absorbent interlabial device disclosed in U.S. Pat. No.5,968,026, which issued to the Procter & Gamble Company, and which isincorporated by reference herein. A commercially available example ofthis pad is the Envive Miniform.

However, the invention is not limited to these specific particularlydisclosed embodiments, which are only given by way of illustration. Anyconfiguration of the pad is possible, which allows it to be capable ofbeing substantially retained in the interlabial space by engagement withthe labial folds, but can be simply and easily removed by manuallyremoving it. Alternatively, the pad can be displaced by the applicationof liquid pressure during urination.

The retention of the pad in the interlabial space permits sustainedcontact between the pad and the labial skin, for sustained delivery ofan active agent to the labial skin. Either local delivery to the labia,intravaginal delivery, or transdermal systemic delivery of drugs can beachieved. In particular embodiments, a method is disclosed for treatinglabial and vaginal inflammations by inserting the pad between the labia,against the external vaginal orifice.

In some embodiments, the method delivers therapeutic substances (such asantibiotics, topical anesthetics or topical anti-fungal medication), forexample in the treatment of vaginitis or dermatitis. The method includespositioning the interlabial pad such that the pad is retained betweenthe labia external to the subject's vagina. The anterior portion of thepad is designed for insertion of the pad between the subject's labia inthe anatomic interlabial space adjacent to the vaginal orifice, and theposterior portion is retained between the labia without the need foradhesive or other attachment devices, as in FIG. 32B. Alternatively, aportion of the pad can project into the vagina, for example to improveretention and enhance intravaginal delivery of an agent.

The pad can be any of a variety of shapes, and particularly shapes whichtaper toward an anterior or leading edge of the pad. The anterior edgeis often sufficiently wide to be retained outside the vaginal orifice,but can be sufficiently narrow to extend at least partially within thevagina (for example no more than 1 inch into the vagina, and in someexamples less than ½ inch). When the pad is substantially or completelyretained external to the vagina, the posterior edge impinges against thesurrounding labia to retain the pad in place. The pad can be symmetricor asymmetric, rounded or elongated, tapering or non-tapering, folded ornot folded. However particular embodiments taper from a relativelylarger posterior portion to a relatively smaller anterior portion. Theenlarged posterior portion is often large enough to at least slightlydeform the surrounding labia to improve frictional engagement betweenthe labia and the pad. The relatively small anterior portion may in someexamples be closer to the width of the vaginal orifice, and is morecomfortably retained in the narrow interlabial space adjacent thevaginal orifice. The pads with a bipartite structure (with a major andminor portion) further enhance the comfort and retention of the pad.

The approach disclosed herein takes advantage of an interlabial route ofadministration, through an accessible, non-parenteral route, which ishighly perfused with a well-developed blood supply that avoid first passmetabolism of the drug in the liver. It is a relatively non-invasiveroute (for example, avoiding the risks of IV non-parenteraladministration), that takes advantage of high permeability for apenetrant having physiochemical characteristics that allow it to passthrough the epithelial covering of the labia.

The permeability of vaginal epithelium has been found to besignificantly greater than many other trans-mucosal routes, and the ILPcan be used to deliver drugs intravaginally as well as to the vulvar orlabial structures. The delivery device can therefore carry active agentsfor local or systemic effects. Examples of drugs suitable for deliveryusing the ILP are agents that are designed to exert a local effect, suchas barrier contraception, treatment or prevention of infection, orestrogenization of vaginal epithelium. Examples of systemicpharmaceutical agents that can be delivered include steroid hormones forcontraception or estrogen/hormone replacement therapy, oranti-infectives (such as antibiotics). The vaginal route is alsobelieved to be an efficient route for the delivery of peptide andprotein drugs, that are becoming increasingly important elements of thetherapeutic armamentarium.

The interlabial delivery device can also be used in conjunction withother forms of drug delivery, such as topical ointments or creams, orintravaginal suppositories. For example, the ILP can be put in placeafter application of an external ointment or cream, or after insertionof the suppository, to increase comfort and decrease leakage or stainingof garments. The ILP can be used, for example, with mucoadhesive drugsor solid hydrogels.

The following definitions and methods are provided to better define thepresent invention and to guide those of ordinary skill in the art in thepractice of the invention. As used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a material” includes a plurality of such materials, and reference to“the absorbent material” includes reference to one or more materials,and so forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention belongs.

Definitions

Absorbent: A material with sufficient absorbency to absorb and retainexudates discharged from a subject. Absorbency is dependent partially onthe physical volume of the device. In a specific non-limiting example, amaterial is absorbent if it absorbs at least 3 ml of 0.9% saline,however an absorbent material may have a capacity of 20 grams or more.

Agent: A substance capable of producing a physical, chemical orbiological effect. Examples of agents include drugs (therapeutic agents)and diagnostic reagents (diagnostic agents). Examples of drugs includeantimicrobial agents (such as the anti-fungal agent miconazole,anti-viral acyclovir, or anti-biotic metronidazole). Examples ofdiagnostic agents include monoclonal antibodies (such as monoclonalantibodies that recognize human papillomavirus (HPV) or herpes simplexvirus (HSV), or chemical reagents in which a reaction occurs in thepresence of a pathogen of interest, such as a color change).

Biodegradable material: A material having greater than or equal to about70% biodegradation (percentage of theoretical carbon dioxide evolution)after 28 days when measured by a suitable test such as the Sturm test(Method 301B, Organization of Economic Cooperation and Development).

Diagnostic test: Any procedure performed on a sample collected from asubject, wherein the procedure can be used to evaluate or monitor adisease or a disorder in the subject. A diagnostic test can be performedin a laboratory, a medical office or in the home environment.

Flushable: A product's capacity to pass through typical commerciallyavailable house toilets and plumbing drainage systems without causingclogging or similar problems that can be directly associated with thephysical characteristics of the product.

Larger and smaller portions: The major portion of the pad is a largerportion, and a minor portion is a smaller portion. Large and small canbe defined, for example, in terms of cross-sectional area, volume, ortransverse dimension. In some embodiments, the pad is inserted betweenthe labia with the minor portion as the leading edge inserted, in whichexample the minor portion would also be considered an anterior edge andthe major portion would be a posterior portion.

Medicinal Agent: A therapeutic agent for treatment of the interlabialspace, perivaginal region, vagina, and/or for regional or systemicdelivery. Specific, non-limiting examples of a medicinal agent areanesthetics, antibiotics, deodorants, or lubricants.

Supporting garment: A garment such as a belt or article of clothing, forexample underwear, used to hold an absorbent pad in place on or in thebody, for example in the vaginal triangle.

Vaginal orifice: The opening of the vagina at the perineum.

Embodiment of FIGS. 1-3

A first embodiment of the invention is shown in FIGS. 1-3. FIG. 1illustrates the urogenital anatomy of a female. Interlabial space 32 isapproximately bounded by the labia majora 34. Anatomical structuresfound within the interlabial space include the labia minora 36, vaginalorifice 38, urethral orifice 40, and clitoris 42. The perineum is a termthat often refers to the pelvic outlet that gives passage to theurogenital ducts and anus, but it is sometimes used in a more restrictedsense to refer to the area 44 which lies between interlabial space 32and the anus 46.

FIG. 2 is a sagittal section of female urogenital anatomy, andillustrates that in this embodiment of the invention, interlabial pad 30is positioned in interlabial space 32 approximately adjacent labiamajora 34, vaginal orifice 38, and urethral orifice 40.

In the embodiment disclosed in FIGS. 2-3, interlabial pad 30 is anelongated absorbent member, for example made of cotton, and has abipartite profile with a major portion 50 and a minor portion 52. In theillustrated example, the major and minor portions each have a crosssection that is a portion of a circle, where the portion of the circleof the major portion 50 has a greater diameter than the portion of thecircle of the minor portion 52. The curvature of the minor portion isgreater than the curvature of the major portion. The overall shape ofpad 30 therefore includes a rounded major portion and a rounded minorportion, in which the transverse diameter or width W1 (FIG. 3) of themajor portion is greater than the transverse diameter or width W2 of theminor portion, so that the width of pad 30 tapers in the direction ofminor portion 52.

The width of major portion 50 is sufficient to fit comfortably and beretained without adhesives within the interlabial space. Minor portion52 has a reduced width (and increased taper) to minimize pressure anddiscomfort in the area of vaginal and urethral orifices 32. The minimumwidth of minor portion 52 is, in some embodiments, substantially thesame or slightly less than the maximum diameter of vaginal orifice 38.The outer profile of both the major and minor portions may be arcuate tohelp conform to surrounding body tissues. The cross-sectional area ofminor portion 52 in some embodiments is less than 50% of thecross-sectional area of pad 30, and has a cross-sectional area that is,for example, 10 to 49% of the total cross-sectional area of pad 30.

The reduced width of minor portion 52 makes interlabial pad 30 easier toinsert and use. Labia majora 34 and labia minora 36 are spread aparteither by moving them apart, or by introducing the reduced width minorportion 52 as a leading edge of the pad between them, and advancing thepad toward vaginal orifice 38. As pad 30 is inserted into interlabialspace 32, the leading minor portion 52 gradually moves labia majora andlabia minora apart, to facilitate acceptance of major portion 50. Onceminor portion 52 is in place against vaginal orifice and urethralorifice 32, major portion 50 provides an enlarged retention member thatfrictionally engages surrounding portions of labia majora 34 to retainmedicinal interlabial pad 30 in position. In this position, interlabialpad 30 is able to deliver an effective amount of an agent to theinterlabial space. The agent may provide its effect within theinterlabial space, regionally, and/or systemically.

The pad is easily inserted between the labia majora and is easilyretained in the interlabial space without the need for auxiliaryretaining means. Thus, a light pressure on the major portion 50 willcause the smaller minor portion 52 to open the labia majora slightly andallow pad 30 to take its proper position in the interlabial space. Theradii of the respective portions are such that the interlabial space 36is substantially or completely occupied by the pad. The elongated padextends along the interlabial space, such that the length of the padhelps frictionally engage the pad and enable it to resist dislodgement.

In particular embodiments, the pad is formed of a soft absorptivematerial such as cellulose, cotton, or another suitable natural orsynthetic fiber or sheeting. In one embodiment the pad is flushable, andcan be made of biodegradable material. The pad may be made as describedin U.S. Pat. No. 5,575,047, herein incorporated by reference. Thisnonabsorptive material may enhance delivery of the medicinal agent fromthe pad to the interlabial mucosa, while minimizing absorption ofvaginal fluids.

Examples of Alternative Embodiments of Pads

Some other examples of alternative embodiments of the pad with atapering portion are shown in FIGS. 4-28. Many of these embodiments areshown in cross-section as relatively flat, although they can beelongated (as indicated by the fragmentary depiction in each Figure).

In the embodiment shown in FIG. 4, a one piece absorptive pad 58 has a“tear-drop” or ovoid cross sectional shape which tapers progressively toa leading anterior edge portion 60 of limited transverse dimension froma posterior portion 62 of relatively large transverse dimension.

The pad 58 may be elongated transverse to the illustrated cross-section,or it may not be elongated (such that the length of the pad transverseto the cross section is less than the anterior-posterior dimension A-Pof the cross-section). In elongated embodiments, the pad may be ofuniform cross section along the length thereof, or may be tapered fromone end to the other end thereof, and in particular embodiments, istapered in its anterior-posterior dimension AP. The user may readily andquickly insert the pad 58 into the interlabial space by introducingleading anterior portion 60 into the interlabial space. The pad isfirmly self retained in the space and exhibits substantial absorptivecapacity for discharges, and resists accidental dislodgement from theinterlabial space.

Other embodiments of the pad are shown which have posterior majorportions of a polygonal (for example quadrilateral) shape, such asrectangular or square. Thus, as shown in FIG. 5, pad 62 includes aposterior portion 64 having flat bottom and side surfaces; and theanterior minor portion 66 has surfaces 68 which incline toward oneanother toward a leading edge 70. Anterior portion 66 therefore forms awedge that parts the labia as it is introduced between them.

FIG. 6 shows a pad 72 that includes a posterior portion 74 ofsubstantially square cross section; and a fingerlike anterior portion 76of limited transverse dimension, which is much narrower than thecorresponding transverse dimension of posterior portion 74. The juncture78 of portions 74, 76 forms an essentially flat shoulder that extendstransverse to the anterior-posterior dimension AP. In the disclosedembodiment, the anterior-posterior dimension of anterior portion 76 issubstantially the same as the anterior-posterior dimension of posteriorportion 74. The slender projecting finger of this pad can be configuredto project through the vaginal orifice and into the vagina when theinterlabial pad is in place. As discussed in detail below, theprojecting finger can carry a pharmaceutical agent designed for vaginaldelivery.

FIG. 7 shows a pad 80 that is similar to that of FIG. 8, except that thesides of anterior portion 84 diverge away from top edge 86, to present amore tapered profile. FIG. 8 shows a pad 88 having a posterior portion90 and an anterior portion 92, wherein both portions are substantiallyquadrilateral in shape, except for a sloping flat shoulder 94 at thejuncture of portions 90, 92. FIG. 9 shows a pad 95 that includes aposterior portion 96 of quadrilateral shape and an anterior portion 98having upwardly converging side surfaces 100 and a flat leading edge102.

While the pads shown in FIGS. 5-9 have posterior portions with flatbottom surfaces, the bottom surfaces may have other configurations.Thus, as shown in FIG. 10, the posterior portion P has an arcuate bottomsurface A, while in FIG. 11, the posterior portion P′ has convergingsurfaces C and an arcuate bottom edge B.

Further, alternative embodiments are shown in FIGS. 12 and 13. Thus, inFIG. 12, the non-bipartite pad 104 is of generally triangular crosssection, with a posterior portion 106 of large cross section and ananterior portion 108 of small cross section. The pad 104 has flat,converging surfaces 110, a slightly curved bottom surface 112, roundedbottom edges 114 and a rounded leading edge 116. The pad 118 shown inFIG. 10 is similar to pad 106, except that the anterior portion 120 istransversely constricted and provides a linear juncture J betweenposterior portion 122 and anterior portion 120. This is an example of abipartite pad that has major and minor portions.

FIG. 14 shows pad 124 which includes a posterior portion 126 ofsubstantially hexagonal cross section and a transversely constrictedanterior portion 128 with a rounded leading edge 130. The surfaces ofposterior portion 126 are flat and edges thereof may be rounded.

FIG. 15 shows pad 132 which includes a posterior major portion 134defined by opposed convergent flat surfaces 136 and a slightly roundedbottom surface 138; while anterior minor portion 140 is of a triangularcross section.

The pads may be suitably tapered in a longitudinal direction transverseto the AP direction. Thus pad 142, as shown in FIG. 16, has its anteriorportion 144 and posterior portion 146 tapered in respect of both thelongitudinal and transverse axes thereof; whereas in pad 148, as shownin FIG. 17, anterior portion 150 and posterior portion 152 are taperedlongitudinally only.

FIG. 18 shows yet another embodiment of the pad 154, in which theanterior portion 156 and posterior portion 158 are substantially ovoidin cross-section, with the transverse width of anterior portion 156 muchless than the transverse width of posterior portion 158.

The pads may be further modified, as shown in FIGS. 19-21. Thus, asshown in FIG. 19, the pad 160 has its posterior portion 162 sloped atone end as at 164, to make the pad conform to the anatomy of the user.Alternatively, as shown in FIG. 20, the pad 166 may be sloped at bothopposite ends 168, 168′. Alternatively, as shown in FIG. 21, pad 170 hasits posterior portion 172 sloped at opposite ends in a convergentconfiguration. If desired, in the foregoing embodiments, the anteriorportions of the pads may also be sloped to converge toward one another.

FIG. 22 shows an embodiment of a pad 174 that has an anterior portion176 and posterior portion 177. The posterior portion 177 is formed witha longitudinal groove 178 of normally triangular section, forming wings180. When the pad 174 is inserted into the interlabial space, as shownin FIG. 23, the wings 180 are resiliently urged toward each other andbear against the labia majora, thereby increasing the retention of thepad within the interlabial space.

The various forms of pads set forth above may also include the groove inthe anterior portions thereof. The pads set forth above which haveopposed flat surfaces (e.g. FIGS. 6-9), are particularly adapted toconform to the medial surfaces of labia majora, thereby optimizing padretention and drug delivery. Such embodiments that have slenderprojecting anterior portions can also be configured such that theanterior projection inserts into the vaginal opening, to further enhanceretention of the pad, or delivery of an agent to the vagina.

Although some of the pads have been shown to taper longitudinally fromone end to the other end, they may also taper from a central portion tothe opposite ends thereof. Thus, while the pad may be of uniform crosssection throughout its length, it may also have a tapered form. Nostring or other removal aid is required, and the pad can be removedmanually, such as with a gentle tap.

Another embodiment of the medicinal interlabial pad 182 is shown in FIG.24, in which the pad 182 has a posterior portion 184 and anteriorportion 186, each having a cross section that defines a portion of acircle. Each of the posterior and anterior portions is a portion of asphere that is symmetric in all directions with respect to a centerpoint, and has a constant radius. For example, posterior portion 184 issymmetric with respect to center C1, while anterior portion 186 issymmetric with respect to center C2.

FIG. 25 shows yet another embodiment of a pad 188 having merged portions190, 192 which are of part elliptical cross section; the portion 190having major and minor axes somewhat larger then those of portion 192,which also lends itself to easy insertion and removal. Portion 190 issymmetric in all directions with respect to perpendicular planes ofsymmetry, one of which is shown as P in FIG. 25. In this embodiment, thepad is not elongated in any direction, although in other embodimentslongitudinal elongation is possible.

The pad 194, shown in FIG. 26, is of an elliptical cross section. Thisembodiment lacks a major portion and a minor portion, and instead has across-section that is completely symmetric with respect to ananterior-posterior plane AP. In use, pad 194 is inserted along the APaxis into the interlabial space (either narrowed end of the pad can bethe leading edge of insertion).

The pad 190 shown in FIG. 27 is an elongated version of the pad in FIG.24 which has a more spherical configuration. Pad 190 in FIG. 27 isinitially of a round cross section, but is formed into a larger andsmaller portion by using a mechanical binding agent, such as thread orheat welding, similar to that described in Gerstenburger (U.S. Pat. No.5,575,047). Alternatively, it can be sewn along the junction between thetwo portions with biodegradable thread, so that the pad is completelybiodegradable, and can be flushed down a toilet. Biodegradable pads canbe made by any method, such as those disclosed in U.S. Pat. No.5,575,047, which is incorporated herein by reference.

In certain examples, the absorbent pads are additionally (oralternatively) impregnated with selected scents, to mask the odor of themedication or any discharges, thereby providing a soothing and pleasantodor. In one embodiment, the pad is impregnated with medication in theanterior (or minor) portion only (that fits closest to the vaginalopening), or in the posterior portion only. In other embodiments, boththe anterior (or minor) and posterior (or major) portions areimpregnated with the medication. Alternatively, the anterior portion maybe impregnated with medication, and the posterior portion is impregnatedwith an odor absorbing or masking agent, or vice versa.

In one embodiment, the pad includes a groove in the anterior orposterior portion, and the scent, medication, or another agent is addedwithin the groove or impregnated in the pad adjacent to the groove.However, in other embodiments the medication is introduced into the padby applying it as a liquid or powder to the pad. Depending on the dosageto be administered, the condition to be treated, the medication to bedispensed, and other factors, the drug or other active agent can beintroduced on to the surface of the pad, impregnated throughout it, orintroduced into superficial regions of the pad, or parts of it.

FIG. 27 shows a cross-section of an embodiment of an elongated absorbentpad 200 that has been modified to carry and dispense pharmaceuticallyactive agents alone or in admixture with deodorants, lubricants, and thelike. The principles of the elongated embodiment could, however, beadapted to the non-elongated embodiments of the type shown in FIG. 24.In the embodiment shown in FIG. 27, pad 200 includes posterior portion202 and anterior portion 204, which is formed with a groove 206extending longitudinally along the top of anterior pad portion 204. Thegroove is prefilled with a material 208, for example, with an ointment,lubricant or other carrier for admixed medications, deodorants and thelike. Placing the interlabial pad in the interlabial space, withanterior portion 204 adjacent to the vaginal orifice and urethralorifice, causes the normal transverse constriction of the pad 200 (andparticularly compression of anterior portion 204) to dispense materialswhich have a suitable viscosity, to the interlabial space, and to thevagina which opens into the interlabial space.

It has been found that the curvilinear surface portions and thenon-uniform cross sections of the several pads shown herein, is highlyeffective in positioning the pad in the interlabial space and retainingit in place. Further, there is no tendency to uncomfortably force thelabia majora apart or to exert undue pressure against their medial wallportions.

In an additional embodiment, the pads are used to absorb discharge fromthe structures within the interlabial space, such as the urethra,vagina, and vulvar epithelium. A diagnostic test is then performed onthe absorbed discharge. In one embodiment, the discharge is a bodilyfluid, such as blood or a secretion, such as a secretion derived fromthe reproductive system. In yet another embodiment, the dischargeincludes cells, such as cells of the vulvar, vaginal or cervicalepithelium, and the cells are analyzed using a diagnostic test. Thediagnostic test can be performed directly on the discharge absorbed bythe medicinal interlabial pad, or the discharge or a component of thedischarge can be extracted from the interlabial pad prior to performingthe diagnostic test (see U.S. Pat. No. 5,094,956).

The diagnostic test can detect, for example, the presence or absence ofa cell type (e.g. see U.S. Pat. No. 5,124,252; U.S. Pat. No. 5,965,375),a protein (e.g. see U.S. Pat. No. 5,190,881; U.S. Pat. No. 5,661,010),or a nucleic acid (e.g. see U.S. Pat. No. 5,538,851; U.S. Pat. No.5,459,034) in the vaginal discharge. The diagnostic test can also beused to detect blood (see U.S. Pat. No. 4,920,045; U.S. Pat. No.5,563,071), or the presence of a virus, such as human papillomavirus(HPV), or a microorganism, such as a pathogen (see U.S. Pat. No.5,705,332; U.S. Pat. No. 5,627,275). The diagnostic test can be aqualitative, semi-quantitative, or quantitative test. In one specific,non-limiting example, the diagnostic test is used to detect a biologicalparameter associated with cervical cancer.

In a specific, non-limiting example, vaginal and vulvar discharge iscollected on the pad and a diagnostic test is then performed on thedischarge to detect human papillomavirus (HPV) infection. For example,the diagnostic test can detect the presence of HPV nucleic acid (seeU.S. Pat. No. 5,580,907; U.S. Pat. No. 5,876,922; U.S. Pat. No.5,783,412; U.S. Pat. No. 5,447,839; U.S. Pat. No. 5,283,171).Alternatively, the diagnostic test can detect the presence of a proteinassociated with HPV infection (see U.S. Pat. No. 5,045,447).

In one embodiment, a kit is provided for administering the medicationfrom the drug delivery device. The kit includes an interlabial pad, anda package such as a plastic vial or a plastic or foil container, forpackaging the interlabial pad. The kit can also include directions forthe use of the pad. The pad can contain a unit dose of the medication,for example an anti-infective, such as gynelotrimin. Another example isthe delivery of estradiol to treat vaginal atrophy or for hormonereplacement therapy (HRT). In HRT, and ILP system releasing 100 mg/dayof estradiol as its 3-acetate ester maintains a circulating plasmaconcentration of 300 pmol/L of the drug, which is within the clinicallydesirable range for HRT.

Examples of other therapeutic agents that could be delivered using thissystem are the delivery of 20 micrograms/day ethinyl estradiol tohypoestrogenic subjects for peak bone mass acquisition duringadolescence; 200 micrograms/day of 17 β-estradiol to relieve severepost-menopausal symptoms; 400 micrograms/day of the GnRH agonistnafarelin for 4 weeks in the initial treatment of endometriosis,followed by half-dose therapy (200 micrograms/day) for 20 weeks; localdelivery of levofloxacin for the treatment of chlamydia trachomatis; ordelivery of 1% flutrimazole for the treatment of fungal infections.

FIG. 29 shows a particular embodiment wherein an interlabial pad isformed of a polypropylene or polyester non-woven fabric with a rayonsliver core. The interlabial pad has an overall length L of about 15 toabout 75 mm, and an overall height H of about 19 to about 22 mm. Of theoverall height of the interlabial pad, the anterior portion AP of theinterlabial pad has a height APH of about 4 to about 7 mm. The posteriorportion PP of the interlabial pad has a height PPH of about 12 to about18 mm. In addition, posterior portion PP of the pad has a width PPW ofabout 8 to about 10 mm. Anterior portion AP has a width APW less thanwidth PPW of posterior portion PP of the pad. In one specific,non-limiting example, width PPW of posterior portion PP of theinterlabial pad is from about 4 to about 7 mm. Posterior portion PP ofthe pad is demarcated from anterior portion AP of the pad by stitchingS. In one specific, non-limiting example the stitching is standard 401chain stitch of about 8-10 SPI.

EXAMPLE 1

Method of Making the Pad

In one embodiment the application devices, such as pads, are molded orotherwise formed from the cellulose base material, to the desired crosssectional and longitudinal configurations by apparatus and proceduresknown in the art, or formed as described in Gerstenburger. The activeagent (such as the drug or diagnostic reagent) can, for example, beapplied in a liquid form by a liquid applicator, between the dancer andpuller.

A specific example of a liquid application system 400 is shown in FIG.33, in which the rope to make a pad passes through a sewing station 402,a puller 404, and a dancer 406. Interposed between puller 404 and dancer406 is a liquid applicator 408, which includes an applicator head 410,mounted on a stand 412, and connected to a source of liquid through aflexible conduit 414.

A more detailed example of liquid application system 400 is illustratedin FIG. 34, which includes a bulk tank 420 to hold the liquid to beapplied, a conduit 422 connecting tank 420 to a pump motor 424 and a 3way valve 426, which controls access to a pair of dispensing tanks 428,430. Liquid application lines 432, 434 lead from opposite ends of valve426 to a dispensing three-way valve 436, which in turn communicates withflexible conduit 414 that leads to applicator head 410.

A source of pressurized air 440 is connected through an air manifold 442to a pressure valve 444, which controls flow of pressurized air throughpressure lines 446, 448 that communicate respectively with dispensingtanks 428, 430. A vacuum generator 450 is also connected through avacuum manifold 452 to a vacuum valve 454, which controls drawing avacuum through vacuum lines 456, 458 that communicate respectively withdispensing tanks 428, 430.

A computer operated controller 460 controls applicator system 408, andintegrates its operation into the operation of the pad manufacturingprocess. In particular, controller 460 communicates with a motorcontroller 462, which in turn communicates with pump motor 424. Thecontroller also communicates with and controls the other components ofsystem 408, such as dispensing tanks 428, 430, pressure valve 444, andvacuum valve 454.

In operation, controller 460 actuates pump 424 to draw liquid from bulktank 420 and introduce it into dispensing tanks 428 or 430, depending onthe position of valve 426. Vacuum generator 450 can also be actuated toremove air from the tank prior to introduction of liquid into dispensingtanks 428, 430, to facilitate filling of the tanks. Sensors withindispensing tanks 428, 430 determine when the tanks are full, and sendthis information to controller 460 to turn off motor 424. Controller 460can actuate pressurized air source 440 to introduce pressurized air intodispensing tanks 428, 430 to assist in the flow of liquid from the tanksthrough valve 436 and into flexible conduit 414. The pressurized liquidis then sprayed out of dispensing head 410 on to the pad. Sincecontroller 460 also monitors the manufacturing line, the rate ofapplication of the liquid can be increased or decreased corresponding toan increase or decrease in the speed of the production line.

EXAMPLE 2

Method of Using the Pad

In use, some embodiments of the application device, such as the pad,would be inserted into the interlabial space and retained for asufficient period of time to deliver the active agent, or allowsufficient time for reaction with a diagnostic reagent. If the activeagent is a diagnostic agent (such as a monoclonal antibody), then thepad could be retained for a period of minutes to allow the reaction tooccur. If the agent is a drug intended for topical application (such asthe anti-fungal agent miconazole), then the pad is retained in place fora sufficient period of time, for example 30 minutes to 4 hours, to allowthe miconazole to be transmitted to the adjacent labial skin and vagina.Alternatively, if the drug is intended for transdermal delivery (forexample of estrogen) then a longer period of transfer may be desired, inwhich the pad is retained for at least one or two hours. If the pad isremoved before the desired period of time has elapsed (for examplebecause the subject needs to urinate), then it can be temporarilyremoved and replaced. Alternatively, a new pad can be inserted.

In other embodiments, a topical preparation is applied to the labia,followed by insertion and retention of an interlabial pad to retain thetopical preparation (such as a cream or ointment) in contact with theskin, and inhibit transfer of the medication to clothing or adjacentskin. Alternatively, a medicated vaginal suppository is insertedintravaginally, and the device is placed intralabially to inhibit lossof medication, or soiling of garments. In yet other embodiments, thedevice includes an intravaginal portion (such as a suppository, anintravaginal portion of the pad, or an intravaginal probe) whichdelivers a therapeutic or diagnostic agent intravaginally, and anextravaginal portion (such as an ILP) which helps retain the device inplace, and prevents loss of the agent from the vaginal opening.

In view of the many possible embodiments to which the principles of theinvention may be applied, it should be recognized that the illustratedembodiments are only particular examples of the invention and should notbe taken as a limitation on the scope of the invention. Rather, thescope of the invention is defined by the following claims. We thereforeclaim as our invention all that comes within the scope and spirit ofthese claims.

1. An interlabial delivery device comprising a delivery material,wherein the device is configured to be retained between labia of asubject, and the device carries a therapeutically or diagnosticallyeffective amount of a diagnostic or therapeutic agent.
 2. The device ofclaim 1, wherein the delivery material is a pad configured to beretained between labia of the subject.
 3. The device of claim 2, whereinthe pad is a highly absorbent non-swellable material.
 4. The device ofclaim 2, wherein the pad has a uniform cross-section along its entirelength or is tapered along its length.
 5. The device of claim 2, whereinthe pad has a minor portion superimposed on a major portion, the minorportion having a cross-sectional area smaller than a cross-sectionalarea of the major portion and wherein the minor portion is tapered tofacilitate insertion between the labia and retention in the interlabialspace.
 6. The device of claim 5, wherein the minor an major portions ofthe pad have a elliptical cross-section with a major axis, wherein themajor axis of the minor portion is less than the major axis of the majorportion.
 7. The device of claim 1, wherein the delivery materialincludes an agent for absorbing odors.
 8. The device of claim 1, whereinthe agent is a diagnostic agent.
 9. The device of claim 1, wherein theagent is a therapeutic agent.
 10. The device of claim 1, wherein thedelivery device comprises an intravaginal portion and an extravaginalportion, and the intravaginal portion carries the agent to be delivered.11. The device of claim 1, wherein the agent is an antibiotic oranti-fungal agent.
 12. The device of claim 1, wherein the agent is ahormone.
 13. The device of claim 1, wherein the agent is a transdermalagent.
 14. The device of claim 1, wherein the agent is a drug is in aunit dosage form.
 15. A method of treating a disease, comprising:positioning a device configured to be retained between labia of asubject in an interlabial space of a subject in need of the therapeuticagent to treat the disease, wherein the device is a pad which carries atherapeutically or diagnostically effective amount of an active agent,or the agent has already been applied to the labia or administeredintravaginally prior to placing the pad in the interlabial space. 16.The method of claim 15, wherein the device is placed substantiallycompletely external to a vaginal orifice.
 17. The method of claim 15,wherein the pad has a tapered leading edge, and the method furthercomprises inserting the pad into an interlabial space to push the labiaapart as the leading edge of the pad is inserted between the labia. 18.The method of claim 17, wherein the tapered leading edge is positionedagainst the vaginal orifice, and a remainder of the pad has a widthwhich is wider than a normal anatomic interlabial space, such that theremainder of the pad is frictionally engaged and retained by opposinglabia.
 19. The method of claim 17, wherein the pad is elongated.
 20. Themethod of claim 15, wherein the method is a method of locally deliveringthe agent to the perilabial area.
 21. The method of claim 20, whereinthe method is a method of systemically delivering the agent.
 22. Amethod for administering a drug, comprising inserting a pad impregnatedwith the drug into the subject's interlabial space, positioning the padadjacent to the subject's external vaginal orifice, wherein the pad isdevoid of corners and flat surfaces intermediate its ends, and the padhas a minor portion superimposed on a major portion, the minor portionhaving a cross-sectional area smaller than a cross-sectional area of themajor portion, wherein both the minor and the major portion arecurvilinear in cross-section, and wherein the minor portion facilitatesinsertion between the subject's labia and retention in the interlabialspace.
 23. The method of claim 22, wherein the pad is elongated and hasa uniform cross-section along its entire length, or is tapered along itslength.
 24. The method of claim 22, wherein the pad is elongated, andwhen placed in the interlabial space, extends external to the vaginalorifice.
 25. The method of claim 22, wherein the pad carries atherapeutically effective amount of a medicinal agent, and positioningthe pad comprises administering the medicinal agent to the subject. 26.The method of claim 22, wherein the medicinal agent is an antifungalagent or a hormone.
 27. The method of claim 26, wherein the hormone isestrogen or testosterone.
 28. A method for treating a symptom of asubject, comprising positioning an interlabial elongated absorbent padsuch that the pad is retained between the labia external to thesubject's vaginal orifice, wherein the pad comprises a longitudinallyextending major portion and a longitudinally extending minor portionintegrated with the posterior portion, wherein the minor portion has asmaller transverse section diameter relative to the larger transversesection diameter of the major portion, wherein the minor portion isdesigned for insertion of the pad between the subject's labia in theanatomic interlabial space adjacent to the vaginal opening, and themajor portion is attached to the anterior portion such that is retainedbetween the labia, wherein insertion and retention of the pad adjacentto the vaginal opening reduces the symptom.
 29. The method of claim 28,wherein the minor and major portions of the pad have a length greaterthan their width, and the shape of the pad substantially conforms to theinterlabial space in which the pad is retained.
 30. The method of claim29, wherein the pad is held between the labia without adhesive orattachment to a supporting garment.
 31. The method of claim 28, whereinthe major portion of the pad has longitudinally extending, opposed,substantially parallel face portions.
 32. The method of claim 28,wherein the minor portion of the pad has longitudinally extending,opposed substantially parallel face portions.
 33. The method of claim32, wherein the opposed flat face portions of the pad are substantiallyparallel.
 34. The method of claim 32, wherein the opposed flat faceportions of the pad are substantially convergent.
 35. The method ofclaim 31, wherein the minor portion of the pad has longitudinallyextending, opposed substantially parallel face portions.
 36. The methodof claim 35, wherein the opposed flat face portions of the pad aresubstantially parallel.
 37. The method of claim 36, wherein the opposedflat face portions of the pad are substantially convergent.
 38. Themethod of claim 28, wherein the minor and major portions of the pad havea shoulder shaped junction.
 39. The method of claim 28, wherein the padcarries a therapeutically effective amount of a medicinal agent, andpositioning the pad comprises administering the medicinal agent to thesubject to relieve the symptom.
 40. The method of claim 39, wherein themedicinal agent is an anti-microbial or a hormone.
 41. The method ofclaim 28, wherein the pad includes a cavity in which a medicinal agentis placed prior to positioning the pad.
 42. The method of claim 41,wherein the cavity is compressed between the labia when the pad ispositioned.
 43. The method of claim 42, wherein the cavity communicateswith an exterior surface of the pad.
 44. The method of claim 43, whereinthe cavity is a recess in an exterior surface of the pad.
 45. The methodof claim 44, wherein the pad is elongated, and the cavity extendslongitudinally along the pad.
 46. The method of claim 28, wherein themethod further comprises applying medication intravaginally orperilabially prior to or simultaneously with positioning the pad.